SDHB Mutations SDHB-Associated

Updated November 2019

Hereditary Paraganglioma-Pheochromocytoma Syndrome: SDHB Mutations

SDHB-Associated Tumor Risks

Mutations in the SDHB gene are primarily associated with increased risks for neuroendocrine tumors called paragangliomas (PGL) and pheochromocytomas (PCC). While many of these tumors are not cancerous, there is a risk for malignant transformation or other complications such as high blood pressure or stroke, so early detection is important.

SDHB mutations are generally associated with higher morbidity and mortality than mutations in the other SDHx genes.1 They typically predispose to sympathetic PGLs with a high risk of malignancy, and, less frequently, to benign or malignant PCCs and parasympathetic PGLs. The risk to develop PCC/PGL in individuals with SDHB mutations has been estimated to be 77% by the age of 50 years.2

Paraganglioma (PGL): Paragangliomas (PGLs) are neuroendocrine tumors that arise from paraganglia. Paraganglia are a collection of neuroendocrine tissue that are distributed throughout the body, from the middle ear and base of the skull to the pelvis.

 Head and Neck PGL: Approximately 28% of individuals with SDHB mutations will develop a head and neck PGL, which tend to have a lower rate of malignant transformation.3-5 These are generally located in the areas surrounding the carotid body, vagus nerve, and jugulotympanic region.6 While typically nonfunctioning, 5% may hypersecrete catecholamines. Individuals may present with enlarging lateral neck masses, cranial nerve and sympathetic chain compression, dysphonia, hoarseness, pain or cough (depending on the PGL location). Jugulotympanic PGL can also present with tinnitus or hearing loss and otoscopic examination may reveal blue- colored masses behind the tympanic membrane.7

 Thoracic, Abdominal, and Pelvic PGL: Pathogenic SDHB variants are associated with large, aggressive sympathetic PGLs (mostly in the abdomen, pelvis, or thorax) that have a 31%–72% risk of malignancy.2,8 Intra- abdominal and thoracic sympathetic-associated PGLs are generally functionally active with excess catecholamine production; however, 10% are biochemically silent. PGLs in these sites often present with symptoms associated with catecholamine hypersecretion, including elevations in blood pressure and pulse, headaches, palpitations, excessive sweating, and anxiety.4,9

Pheochromocytoma (PCC): These are catecholamine-secreting PGLs confined to the adrenal medulla. It is estimated that 15-52% of individuals with SDHB mutations will develop a PCC.2,4,10,11 These often present with symptoms associated with catecholamine hypersecretion, including elevations in blood pressure and pulse, headaches, palpitations, excessive sweating, and anxiety. Although less common than malignant extra-adrenal sympathetic PGLs, malignant PCC do occur.2

Other Risks: Gastrointestinal stromal tumors (GIST), renal cancer, papillary thyroid carcinoma, and pituitary adenomas have all been reported in individuals with mutations in the four genes encoding the SDH subunit.2,11-14

SDHB Risk Management

It is suggested that individuals with hereditary paraganglioma-pheochromocytoma syndrome have regular clinical monitoring by a physician or medical team with expertise in the treatment of hereditary GIST and PGL/PCC syndromes. A consultation with an endocrine surgeon, endocrinologist, and otolaryngologist is also recommended to establish an individualized care plan.

UT Southwestern Harold C. Simmons Comprehensive Cancer Center | 2201 Inwood Rd., Dallas, Texas 75390-9323 Phone: (214) 645-2563 | Fax: (214) 645-2562 | http://www.utswmedicine.org/cancer/programs/cancer-genetics/ The Endocrine Society has published Pheochromocytoma and Paraganglioma Clinical Practice Guidelines.4 Recommended screening is outlined below. In general, imaging modalities should be at the discretion of the managing provider due to conflicting data regarding the utility and efficacy of the various options. Per the AACR Pediatric Oncology Series, routine screening should begin between the ages of 6 to 8 years.15

SDHB Surveillance Recommendations4,10,14,15 Frequency

Physical Exam  Physical exam (including blood pressure and evaluation for arrhythmia and/or Annually (at palpable abdominal masses) minimum)

Biochemical  24 hour urine fractionated metanephrines and catecholamines and/or plasma Annually Screening for free fractionated metanephrines PGL/PCC o Follow-up imaging by CT, MRI, I-MIBG, or FDG-PET if levels become elevated or if the original tumor had minimal or no catecholamine/fractionated metanephrine excess  Plasma methoxytyramine

Imaging for  MRI/CT of skull base and neck, abdomen, thorax, and pelvis Every 2-4 years PGL/PCC o Unless contraindicated, CT is generally recommended over MRI as a first-choice imaging modality due to its spatial resolution for the thorax, abdomen, and pelvis.

 Periodic 123I-MIBG (metaiodobenzylguanidine) scintigraphy may detect Every 2–4 years paragangliomas or metastatic disease that are not detected with MRI or CT

Renal Cancer  Screening tests for renal cancer can include urinalysis (urine test) to screen for Consider at Screening small amounts of blood in the urine or imaging tests (ultrasound, CT, MRI) clinician discretion

Perioperative Medical Management: Patients should undergo appropriate perioperative medical management including preoperative blockade of hormonally active tumors to prevent perioperative cardiovascular complications.4

Treatment: The management of tumors in individuals with hereditary PGL/PCC syndromes resembles management of sporadic tumors; 4 however, individuals with a SDHB mutation are more likely to have multiple tumors and multifocal and/or malignant disease than are those with sporadic tumors.

Pregnancy Management: Evaluation for PGL/PCC should be performed prior to achieving pregnancy. However, after a diagnosis of PGL/PCC in pregnancy, it is important that delivery be in a tertiary hospital with an experienced obstetric, anesthetic, and endocrine service as well as a neonatal intensive unit.16

Implications for Family Members/Reproductive Considerations

 First-degree relatives (i.e., parents, siblings, and children) have a 50% chance to have the familial SDHB mutation. Second-degree relatives (i.e., nieces/nephews, aunts/uncles, and grandparents) have a 25% chance to have the familial mutation.  For carriers of a known mutation, assisted reproduction (with or without egg or sperm donation), pre- implantation genetic testing, and prenatal diagnosis options exist.  All family members are encouraged to pursue genetic counseling to clarify their risks. Family members can visit www.FindAGeneticCounselor.com to find genetic services near them.

 Pheo Para Troopers (www.pheoparatroopers.org) is a national organization that offers resources, support and advocacy for families facing Hereditary PGL/PCC syndromes.

References

1. Gimenez-Roqueplo AP, Favier J, Rustin P, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer research. 2003;63(17):5615-5621. 2. Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Jama. 2004;292(8):943-951. 3. Benn DE, Gimenez-Roqueplo AP, Reilly JR, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. The Journal of clinical endocrinology and metabolism. 2006;91(3):827-836. 4. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2014;99(6):1915-1942. 5. Bardella C, Pollard PJ, Tomlinson I. SDH mutations in cancer. Biochimica et biophysica acta. 2011;1807(11):1432- 1443. 6. Williams MD, Tischler AS. Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas. Head and neck pathology. 2017;11(1):88-95. 7. Gujrathi CS, Donald PJ. Current trends in the diagnosis and management of head and neck paragangliomas. Current opinion in otolaryngology & head and neck surgery. 2005;13(6):339-342. 8. Costa MH, Ortiga-Carvalho TM, Violante AD, Vaisman M. Pheochromocytomas and Paragangliomas: Clinical and Genetic Approaches. Frontiers in endocrinology. 2015;6:126. 9. Young WF, Jr. Paragangliomas: clinical overview. Annals of the New York Academy of Sciences. 2006;1073:21-29. 10. Welander J, Soderkvist P, Gimm O. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-related cancer. 2011;18(6):R253-276. 11. Ricketts CJ, Forman JR, Rattenberry E, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Human mutation. 2010;31(1):41-51. 12. Pasini B, McWhinney SR, Bei T, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. European journal of human genetics : EJHG. 2008;16(1):79-88. 13. Evenepoel L, Papathomas TG, Krol N, et al. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genetics in medicine : official journal of the American College of Medical Genetics. 2015;17(8):610-620. 14. Muth A, Crona J, Gimm O, et al. Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma. Journal of internal medicine. 2019;285(2):187-204. 15. Rednam SP, Erez A, Druker H, et al. Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017;23(12):e68-e75. 16. Wing LA, Conaglen JV, Meyer-Rochow GY, Elston MS. Paraganglioma in Pregnancy: A Case Series and Review of the Literature. The Journal of clinical endocrinology and metabolism. 2015;100(8):3202-3209.